observational-fear-as-a-model-of-affective-empathy-in-mice

Observational Fear as a Model of Affective Empathy in Mice

Empathy, characterized by the ability to recognize and share the emotions of others, plays a fundamental role in shaping social interactions. It allows ...

Institute for Basic Science (IBS)

Empathy is the important capacity to recognize and share emotions with others. Recent evidence shows that rodents possess a remarkable affective sensitivity to the emotional state of others and that primitive forms of empathy exist in social lives of rodents. However, due to the ambiguous definitional boundaries between empathy, emotional contagion and other related terms, distinct components of empathic behaviors in rodents need to be clarified. Hence, we review recent experimental studies demonstrating that rodents are able to share emotions with others. Specifically, we highlight several behavioral models that examine different aspects of rodent empathic behaviors in response to the various distress of conspecifics. Experimental approaches using rodent behavioral models will help elucidate the neural circuitry of empathy and its neurochemical association. Integrating these findings with corresponding experiments in humans will ultimately provide novel insights into therapeutic interventions for mental disorders associated with empathy.

Rodent models for studying empathy.

Empathy is crucial for our emotional experience and social interactions, and its abnormalities manifest in various psychiatric disorders. Observational fear is a useful behavioral paradigm for assessing affective empathy in rodents. However, specific genes that regulate observational fear remain unknown. Here we showed that 129S1/SvImJ mice carrying a unique missense variant in neurexin 3 (Nrxn3) exhibited a profound and selective enhancement in observational fear. Using the CRISPR/Cas9 system, the arginine-to-tryptophan (R498W) change in Nrxn3 was confirmed to be the causative variant. Selective deletion of Nrxn3 in somatostatin-expressing (SST+) interneurons in the anterior cingulate cortex (ACC) markedly increased observational fear and impaired inhibitory synaptic transmission from SST+ neurons. Concordantly, optogenetic manipulation revealed that SST+ neurons in the ACC bidirectionally controlled the degree of socially transmitted fear. Together, these results provide insights into the genetic basis of behavioral variability and the neurophysiological mechanism controlling empathy in mammalian brains.

A Missense Variant at the Nrxn3 Locus Enhances Empathy Fear in the Mouse.

Empathy enables social mammals to recognize and share emotion with others and is well-documented in non-human primates. During the past few years, systematic observations have showed that a primal form of empathy also exists in rodents, indicating that empathy has an evolutionary continuity. Now, using rodents exhibiting emotional empathy, the molecular and cellular study of empathy in animals has begun in earnest. In this article, we will review recent reports that indicate that rodents can share states of fear with others, and will try to highlight new understandings of the neural circuitry, biochemistry and genetics of empathic fear. We hope that the use of rodent models will enhance understanding of the mechanisms of human empathy and provide insights into how to treat social deficits in neuropsychiatric disorders characterized by empathy impairment.

Observational fear behavior in rodents as a model for empathy.

The neurocognitive ability to recognize and share the mental states of others is crucial for our emotional experience and social interaction. Extensive human studies have informed our understanding of the psychobehavioral and neurochemical bases of empathy. Recent evidence shows that simple forms of empathy are conserved from rodents to humans, and rodent models have become particularly useful for understanding the neurobiological correlates of empathy. In this review, we first summarize aspects of empathy at the behavioral and neural circuit levels, and describe recent developments in rodent model behavioral paradigms. We then highlight different neurobiological pathways involved in empathic abilities, with special emphasis on genetic polymorphisms associated with individual differences in empathy. By directly assessing various neurochemical correlates at molecular and neural circuit levels using relevant animal models, we conclude with the suggestion that rodent research can significantly advance our understanding of the neural basis of empathy. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.

Genetic factors associated with empathy in humans and mice.

Observational fear learning in rodents is a type of context-dependent fear conditioning in which an unconditioned stimulus (US) is provided vicariously by observing conspecific others receiving foot shocks. This suggests the involvement of affective empathy, with several recent studies showing many similarities between this behavior and human empathy. Neurobiologically, it is important to understand the neural mechanisms by which the vicarious US activates the fear circuit via the affective pain system, obviating the sensory pain pathway and eventually leading to fear memory formation. This paper reviews current studies on the neural mechanisms underlying observational fear learning and provides a perspective on future research on this subject.

Neural Basis of Observational Fear Learning: A Potential Model of Affective Empathy.

Optogenetic approaches for controlling Ca channels provide powerful means for modulating diverse Ca-specific biological events in space and time. However, blue light-responsive photoreceptors are, in principle, considered inadequate for deep tissue stimulation unless accompanied by optic fiber insertion. Here, we present an ultra-light-sensitive optogenetic Ca modulator, named monSTIM1 encompassing engineered cryptochrome2 for manipulating Ca signaling in the brain of awake mice through non-invasive light delivery. Activation of monSTIM1 in either excitatory neurons or astrocytes of mice brain is able to induce Ca-dependent gene expression without any mechanical damage in the brain. Furthermore, we demonstrate that non-invasive Ca modulation in neurons can be sufficiently and effectively translated into changes in behavioral phenotypes of awake mice.

Non-invasive optical control of endogenous Ca channels in awake mice.

Empathy, crucial for social interaction, is impaired across various neuropsychiatric conditions. However, the genetic and neural underpinnings of empathy variability remain elusive. By combining forward genetic mapping with transcriptome analysis, we discover that aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a key driver modulating observational fear, a basic form of affective empathy. Disrupted ARNT2 expression in the anterior cingulate cortex (ACC) reduces affect sharing in mice. Specifically, selective ARNT2 ablation in somatostatin (SST)-expressing interneurons leads to decreased pyramidal cell excitability, increased spontaneous firing, aberrant Ca dynamics, and disrupted theta oscillations in the ACC, resulting in reduced vicarious freezing. We further demonstrate that ARNT2-expressing SST interneurons govern affective state discrimination, uncovering a potential mechanism by which ARNT2 polymorphisms associate with emotion recognition in humans. Our findings advance our understanding of the molecular mechanism controlling empathic capacity and highlight the neural substrates underlying social affective dysfunctions in psychiatric disorders.

Article	Year
Rodent models for studying empathy. Neurobiology of learning and memory\| PubMed ID: 27475995	2016
A Missense Variant at the Nrxn3 Locus Enhances Empathy Fear in the Mouse. Neuron\| PubMed ID: 29681532	2018
Observational fear behavior in rodents as a model for empathy. Genes, brain, and behavior\| PubMed ID: 30264490	2019
Genetic factors associated with empathy in humans and mice. Neuropharmacology\| PubMed ID: 30716414	2019
Neural Basis of Observational Fear Learning: A Potential Model of Affective Empathy. Neuron\| PubMed ID: 31600517	2019
Non-invasive optical control of endogenous Ca channels in awake mice. Nature communications\| PubMed ID: 31924789	2020
ARNT2 controls prefrontal somatostatin interneurons mediating affective empathy. Cell reports\| PubMed ID: 39180750	2024

Sehoon Keum

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